From: TSS()Subject: EFSA assessment of the likelihood of the infectivity in SRM derived from cattle at different age groups estimated by back calculation modelling Date: May 11, 2007 at 8:52 am PST

Opinion of the Scientific Panel BIOHAZ on the assessment of the likelihood of the infectivity in SRM derived from cattle at different age groups estimated by back calculation modelling Last updated: 11 May 2007 Publication Date: 11 May 2007

Adopted on 19 April 2007. (Question N° EFSA-Q-2006-002)

The European Food Safety Authority (EFSA) was invited to provide an opinion on the assessment of the likelihood of the infectivity in SRM derived from infected cattle at different age groups, estimated by a back calculation modelling as indicated in “approach 4” in the annex to the Opinion of 28 April 2005 of the Scientific Panel on Biological Hazards on the assessment of the age limit in cattle for the removal of certain Specified Risk Materials.

Following extensive and repeated scientific discussions it appeared that scientific consensus at the back calculation modelling could not be achieved. This possibility was already mentioned in the previous Opinion as one of the limitations of the approach. Therefore, the assessment of the likelihood of the infectivity in SRM derived from cattle at different age groups was based on data of experimental pathogenesis and dose/incubation period studies and on the descriptive epidemiology of BSE with respect to risk populations, to age at infection and age at detection by clinical and active surveillance.

Experimental studies of the distribution of BSE infectivity relative to the period post exposure in cattle have been conducted in the UK and more recently in Germany. Complete data from sequential kill pathogenesis studies and additional data from attack rate studies are now available to provide the basis for a revised calculation on incubation period ranges according to low (1g of fresh brain material obtained from clinical cases) and high (100g) infectivity doses. Moreover, initial data from the German pathogenesis study using the high dose have become available. These studies have used detection of the disease-associated prion protein (PrPTSE) in tissue as a proxy but not perfect surrogate for infectivity.

In view of the the results, the panel considers its earlier opinion of 28 April 2005 still valid, which concluded that the likely detectable infectivity in the CNS appears at about ¾ of the incubation time. The situation has not changed either with regard to tissues comprised of, or containing, lymphoid tissue designated as SRM.

There are now completed pathogenesis data available from the experimental low-dose scenario that appears now more likely to resemble the field situation than an exposure in the field with a high dose of BSE infectivity. If PrPTSE/infectivity is modelled as present in CNS at 75% of the incubation period, as in the previous opinion, it can be predicted that the infectivity would be sub-detectable or still absent in CNS in cattle aged 33 months.However, when interpreting the significance of the experimental data some points require to be considered, including the field occurrence of at least one BSE infected case in animals younger than 33 months in EU cohorts born after 2000, and the problem that failure to detect PrPTSE does not guarantee absence of infectivity in a tissue.

The BSE epidemic is on decline in the different EU Member States, which is linked to a reduction in exposure. However, there is good reason to group member states for separate considerations or as individual cases. To date, the three youngest out of 22 BSE infected cases in cattle born after 2000 were aged 32, 36 and 39 months, respectively. Another case tested positive at an age reported as 25 months but there is uncertainty about its age. The number of cattle infected with BSE is likely to continue to reduce. It is now apparent that cases detected by active surveillance may be closer to clinical onset than previously estimated.

1. The situation has not changed despite some new information with regard to tissuescomprised of, or containing, lymphoid tissue designated as SRM.

2. The medulla oblongata remains optimal for the initial detection of PrPTSE in theCNS.

3. While now more complete data of experimental pathogenesis studies have becomeavailable, the panel considers the earlier opinion of 28 April 2005 still valid,which concluded that the likely detectable infectivity in the CNS appears at about¾ of the incubation time.

4. The results of experimental pathogenesis studies must be interpreted with cautionwith respect to the field situation. With regard to dose, however, epidemiologicaldata is consistent with a low field exposure scenario (equivalent or similar to 1g offresh brain material from clinical BSE cases rather than 100g in theseexperimental studies).

5. The shortest incubation period in bovines experimentally infected by 1g is45 months.

6. If PrPTSE/infectivity is conservatively modelled as present in CNS at 75% of theincubation period, as in the previous opinion, it can be predicted that theinfectivity would be sub-detectable or still absent in CNS in cattle aged 33months.

7. When interpreting the significance of the experimental data the following pointsrequire to be considered:

o At least one BSE infected case has been detected in animals aged 33months or younger in EU cohorts born after 2000.

o Pathogenesis studies show significantly different timing of PrPTSEdetection between dose groups, and wide confidence intervals for the timepoint at 50% detection (in particular in the high dose model).

o Infectivity may be more widely distributed prior to the time of detection ofPrPTSE by routine testing in the CNS (medulla oblongata) after the animalwas exposed to a low (1g) rather than high (100g) dose.

o The cattle experiments of oral exposure to the BSE agent, in common withoral exposure studies in laboratory animals do not provide such consistentincubation times as those obtained with experimental TSE models inrodents using passaged agents, after parenteral exposures.

o The sensitivity of PrPTSE detection is still lower than certain bioassays:failure to detect PrPTSE does not guarantee absence of infectivity in atissue.